Tuesday, April 06, 2010

What is CAL 101?

The hematological world was entranced when in 1999 imatanib (Gleevec in America, Glivec in the rest of the world; pronounced the same however it is spelled) was shown in a phase 1 dose finding study to introduce molecular remissions in chronic myeloid leukemia. Imatanib is an orally active tyrosine kinase inhibitor. There are about 1800 different kinases in the human cell, and the hunt was on for other inhibitors that would work in other forms of cancer.

So far the kinase inhibitors that have been tested have not been as good as Glivec - no, that's not true, there are better inhibitors than Glivec, there hasn't been such a good target as bcr/abl in other cancers.

CAL 101 is a small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K) with potential immunomodulating and antineoplastic activities. It inhibits the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), preventing the activation of the PI3K signaling pathway.

This pathway is illustrated to the left of this schematic diagram, which shows some of the ways that a stimulus to the surface of a cell is transmitted to the nucleus where transcription factors are activated. Trancription factors are responsible for the reading of DNA and the subsequent enactment of its message in the cell. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. Thus it could be seen as targeted towards leukemias and lymphomas, though it would also suggest that suppression of normal hematopoiesis might be a side effect.

An interim report of a phase 1 clinical trial of CAL-101 in patients with relapsed or refractory CLL, indolent non-Hodgkin’s lymphoma (NHL), aggressive NHL, acute myeloid leukemia (AML), and multiple myeloma (MM) was given at last year's IWCLL meeting in Barcelona. At this interim assessment, 29 percent of CLL patients treated at the dose level at which it was decided to expand the cohort had partial responses observed after 28 days of therapy (1 cycle) and 94 percent achieved evidence of biologic activity with a greater than 50 percent shrinkage of lymph node tumors. Five out of six partial responders continue treatment with CAL-101, with the longest response greater than 224 days. All patients had prior rituximab and fludarabine therapy and nearly half of the patients had prior alemtuzamab therapy. Half of the patients were refractory to their last therapy prior to entering the study. A low incidence of hematologic toxicity was observed. The dose limiting toxicity in the study was an elevation of transaminases (ALT and AST), which has been both monitorable and reversible and patients were usually able to resume therapy at a lower dose.

Last month a new trial with Ian Flinn as Principle investigator was begun in CLL. This will be a Phase I Study to Investigate the Safety and Clinical Activity of CAL-101 in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia. The Primary Outcome Measures will be Safety of CAL-101 in combination with rituximab and bendamustine - assessed by adverse events, vital signs, clinical laboratory tests and ECG. The Secondary Outcome Measures will be clinical activity evaluated by clinical response rate - assessed by CT scan, clinical laboratory tests and bone marrow biopsy if indicated; plasma concentrations of CAL-101; plasma concentrations of bendamustine in a select subset of patients; and the pharmacodynamic effects of CAL-101 treatment - assessed by comparing pre and post dose blood samples.

There will be three arms to the study: CAL-101 daily for 12 28-day cycles plus treatment with rituximab for 8 weekly doses over the first 2 cycles (CAL-101 100 mg by mouth twice daily; Rituximab 375 mg/m2 administered intravenously); CAL-101 daily for 12 28-day cycles plus bendamustine on days 1 & 2 of Cycles 1-6 (CAL-101 100 mg by mouth twice daily; Bendamustine 90 mg/m2 administered intravenously); and CAL-101 daily for 12 28-day cycles plus rituximab on day 1 and bendamustine on days 1 & 2 of Cycles 1-6 (CAL-101 100 mg by mouth twice daily; Rituximab 375 mg/m2 administered intravenously; Bendamustine 90 mg/m2 administered intravenously). Inclusion criteria are patients with CLL or indolent lymphoma, previously treated with relapsed or refractory disease (refractory defined as not responding to a standard regimen or progressing within 6 month of the last course of a standard regimen)
and WHO performance status of ≤ 2. Exclusion criteria: Not a good candidate according to the clinical judgment of the investigator; Patients with atypical immunophenotype with t(11:14) translocation or cyclin D1 over-expression; Had radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 4-weeks prior to the baseline disease status tests; Had treatment with a short course of corticosteroids for symptom relief within 1-week prior to the baseline tests; Has had an allogeneic hematopoietic stem cell transplant; Has known active central nervous system involvement of the malignancy; Is pregnant or nursing; Has active, serious infection requiring systemic therapy; Has a positive test for human immunodeficiency virus (HIV) antibodies; Has active hepatitis B or C. Patients with serologic evidence of prior exposure are eligible.

Four centers are registered: Nashvill, NCI, Cornell and St Louis. Details can be found here.

This may not be Glivec but it looks a worthwhile and encouraging agent acting in a way different to anything else that has been tried in CLL.


Randy Shannon said...

As a participant in the ongoing CAL 101 trial, I have seen an increase in my energy and, dare I say- an increase in my hope for the future.

I do appreciate your continued involvement in this endeavor, and the objective comments are extremely valuable.

Here's to hope.

God Bless,

Anonymous said...

Cal-101 is giving at best partial remissions as a sole agent, thus the attempt to improve on that with combination therapy.

I'm not a big fan of bendamustine. I think the long-term side effects will include a heightened chance of MDS and perhaps other cancers. I think hopes for B is over-optimistic.

Anonymous said...

I think the name of the drug is funny. Highway 101 is a famous, and scenic highway/freeway in California that hugs the coast from San Diego to the Oregon border. Cal-101 reminds me of sunny southern California; I suspect the name was chosen deliberately; I doubt that it was the 101st cancer drug Calistoga Pharmaceuticals developed.

Brian Koffman said...

I understand from Dr. Kipps that CAL 101 is the first drug to get out of the test tubes and into people from Calistoga

Charles said...

I have been in the CAL-101 Trial in Nashville, TN since mid-January. My nodes have reduced greatly, and I have more energy.
So far, I am not limited by any side effects. These results are greatly appreciated, after poor results with Chlorambucil, Rituxan, Pentostatin, and Cytoxan.
I believe the different mechanism of cell death is great for the patient.

Charles Hull

Anonymous said...

What do you feel about PET scans in FOllicular lymphomas?

Terry Hamblin said...

PET scans are useful if a tranformation to a higher grade is suspected.

George said...

Thanks a lot. Terry, I'm a huge fan of your blog and agree with almost 99% of your writings. As a consultant having worked for the NHS for a while, I'd like you to comment on time management of our job and the fact that everybody (I felt) would wish to be a bit more clinical rather than managerial-focused. Also, although NICE is doing great job, I think we all would like it to be more flexible.
Thanks again and best wishes and luck for your personal fight...
George from Greece (now).

Anonymous said...

I've been in a Cal-101 trial for about 5 weeks, and my nodes have shrunk considerably. No side effects at this point.

Anonymous said...

CAL-101 is named after the company Calistoga Pharmaceuticals. Calistoga Pharmaceuticals was named randomly during a conversation over the phone. One person was drinking Calistoga flavored water and suggested it. CAL-101 is the 1st compound to come out of Calistoga.

Gabrielle said...

Has there been any output relating to this? My husband has CLL (diagnosed last year) and as you might imagine, I am very tuned into anything relating to possible treatment, etc.

Any information you'd have since this was posted would be great.

Terry Hamblin said...

CAL 101 is excellent at reducing lymph nodes but less good at clearing the blood - that's why most trials now use it in combination. Several trials are running and if you ask your local oncologist, he should be able to direct you towards one.

Ed Marimba said...

A few years ago you recommendation was to avoid chemo as long as possible, and when treatment was inevitable, to try courses of Rituxan first.

I'm at Rai stage 4, although I haven't gotten a FISH yet. I visited a hemo-onc who said that he believed the first line of treatment should be FCR, in order to get a strong remission. He felt that treating first with Rituxan (or I suppose ofatumamab) would tend to hurt the chances later of the effectiveness of general chemotherapy.

I'm wondering if you've read any research on Rituxan ameliorating the effects of subsequent chemotherapy?

Thanks very much!

Terry Hamblin said...

No, things have moved on since I wrote that. I would recommend FCR as first line now.

Unknown said...

Is there any information on risks to those around a patient using Cal-101. How long does it flush out of ones system and can it be toxic to others?